The structure of the infectious form of prion protein, PrPSc, remains unclear. One recent approach to solving protein amyloid fibril structures is cryo-electron microscopy, which has recently been used by other groups to reveal the amyloid core structures of disease-associated tau and synuclein fibrils. We have begun to pursue cryo-electron microscopy-based elucidation of PrPSc structure. Progress has been made, with lateral views and image reconstructions revealing stacked beta sheets running perpendicular to the fibril axis. The spacing between the sheets is 4.8 A. However, so far the resolution obtained has been insufficient to decipher the backbone folding of the core of amyloid fibrils of brain-derived PrPSc.